Mast cells have been implicated in the mediation of inflammatory conditions such as asthma, rheumatoid arthritis and inflammatory bowel disease and the role in allergic inflammation is widely recognized. Mast cells are increased in number in lung explants from severe asthmatics and are the major source of clinically relevant inflammatory mediators such as leukotriences, histamine and Th2 cytokines. Mast cells are the major source of pre-formed TNF in disease tissues.
Stem Cell Factor (SCF) is a glycoprotein that signals through the cell and membrane associated tyrosine kinase receptor hereafter defined as c-Kit, and this signaling pathway plays a key role in hematopoiesis acting both as a positive and negative regulator, often in synergy with other cytokines. A soluble shed c-Kit receptor may play a role in regulating SCF. C-Kit is expressed on pluripotent hematopoietic stem cells which are the precurors to mature cells belonging to lymphoid and erythroid lineages. Unlike other hematopoietic cells, mast cell precursors and mature mast cells retain high-levels of c-Kit expression. Hence SCF signaling via c-Kit is vital for mast cell development, function, trafficking and survival. It also plays a role in gametogenesis, and melanogenesis. Mice with inactivating c-Kit mutations in the W locus have virtually no mast cells. Activating c-Kit mutations in man are associated with mastocytosis.
c-Kit positive pluripotent hematopoietic stem cells are precursors to multiple cell types including mesenchymal cells, fibroblasts and mast cells. Fibrotic disease is characterized in part by excessive fibroblast activity and proliferation resulting in the extracellular matrix deposition. C-Kit positive bone marrow pluripotent hematopoietic stem cells have been reported to be a source of the fibroblasts and mast cells in fibrotic tissues.
Mast cells can provide a sustained source of inflammatory, angiogenic, mitogenic and fibrogenic mediators. Mast cells are functionally and anatomically coupled to fibroblasts and have a direct role in activating fibroblasts. Mast cells increase the kinetics and magnitude of fibroblast mediated collagen contraction, extracellular matrix deposition and can transform fibroblasts into myofibroblasts. Fibroblasts in turn secrete SCF to further activate and expand mast cells, and both cell types are components of the fibrogenic network.
Mast cell number and mast cell mediators are significantly elevated in most human fibrotic diseases including idiopathic pulmonary fibrosis (IPF) and Scleroderma. Differential mast cell phenotypes are detected in some scleroderma patients and in the Tsk mouse model of scleroderma. An aggressive systemic form of mastocytosis may be characterized by myelofibrosis indicating that mast cells can be effector cells in fibrosis.
Gleevec™ and others in the class like Sutent™ are multi-targeted tyrosine kinase receptor inhibitors that can target c-Kit signaling activity, but inhibit a number of other kinases. These kinase inhibitors are indicated for the oncology setting. Myelosuppression, anemia and a number of side-effects including cardiotoxicity and peripheral edema have been reported for Gleevec. Therefore these molecules may not possess the best benefit to risk profile for chronic treatment of diseases associated with c-Kit signaling. Thus, there is a need for new therapies and reagents, particularly those that are more potent and selective, and possess better safety profiles for the treatment of c-Kit associated inflammatory and fibrotic diseases. Such a compound could also show significantly better efficacy and safety profiles in oncologic diseases such as myeloid derived leukemia, diseases associated with c-Kit mutations such as GIST and mastocytosis, diseases associated with over-expression of c-kit and/or excessive SCF autocrine activity as in melanoma and various SCLCs. Therapies and reagents targeting human c-Kit and capable of affecting a therapeutic benefit without significant adverse effects are currently lacking.